Variability in the trajectory of clinical symptoms in the early emerging presentation of young children with autism spectrum disorder (ASD) exists within an individual child over time and between different children at any point in time and across time. Georgiades et al.(1) recently coined the term "chronogeneity" to indicate these within- and between-participant patterns of variability over time. In clinical practice, this is often the focus of questions that parents ask clinicians at or soon after diagnosis : "Can you tell us what the future holds and will his (her) symptoms improve or get worse ?" The variability or heterogeneity within and between children on the autism spectrum makes that a tough question to answer, however well one understands the motivation of the parent or caregiver in asking it.

2. Lord C. For Better or for Worse ? Later Diagnoses of Autism Spectrum Disorder in Some Younger Siblings of Already Diagnosed Children. Journal of the American Academy of Child and Adolescent Psychiatry. 2018 ; 57(11) : 822-3.

Later diagnoses of autism spectrum disorder (ASD) represent a theoretical challenge for researchers, including myself, who have conceived of ASD as a very early arising developmental disorder that affects learning and behavior from infancy onward.(1) Such diagnoses also are a concern because of disparities in access to early intervention, which we know are associated with ethnic minority status and less parental education.(2) If we believe that early intervention makes a difference, then finding children with ASD who cannot be identified until early school age is problematic. Three recent studies, before the present study by Ozonoff et al.,(3) found relatively small, but not insignificant, numbers of children who were not diagnosed until after 6 years of age.(4-6) The present study by Ozonoff et al.(3) uses the opportunity provided by a unique prospective dataset of younger siblings of children with autism (often referred to as the Baby Siblings Research Consortium) to describe 14 children who had not been identified as having ASD at 3 years of age, despite detailed early assessments by a skilled research team, out of 113 children who received ASD diagnoses in middle childhood.

Evidence from genetic, animal, and epidemiologic studies have consistently implicated the serotonin (5-HT) system as an important risk factor for autism spectrum disorder (ASD).(1) Hyperserotonemia has been documented in more than 25% of pediatric ASD cases.(2) Although serotonergic functioning is a plausible and tantalizing component of causal models of ASD pathophysiology, specific mechanisms remain poorly understood.(2) Barriers to delineating these mechanisms include the difficulty of disentangling the effects of genetic risks, environmental exposures across development (including gestational exposure to selective 5-HT reuptake inhibitors),(3) and the possible interactions between these factors in a population with considerable phenotypic and prognostic heterogeneity.

OBJECTIVE : There is a prevailing notion that children with autism spectrum disorder (ASD) exhibit intense negative and attenuated positive emotions, although the empirical evidence regarding their emotional expressiveness (EE) is limited. Given the importance of emotions in shaping social and cognitive development, we examined intensity and valence of EE and links between EE and autism severity and parent-reported temperament in ASD. METHOD : Toddlers (aged 21.2 months) with ASD (n = 43), developmental delay (DD, n = 16), and typical development (TD, n = 40) underwent standardized probes designed to induce anger, joy, and fear. Intensity of EE through facial and vocal channels were coded offline. Autism severity and temperament were quantified using the Autism Diagnostic Observation Schedule-2 (ADOS-2) and Early Childhood Behavior Questionnaire (ECBQ). RESULTS : The ASD group exhibited less intense fear compared to both the DD and TD groups, more intense anger than DD but not TD, with no differences in joy intensity. All groups showed similar levels of incongruous negative EE. Intensity of fear and anger were not associated with severity of autism symptoms, but lower intensity of joy was related to greater autism severity. Expressed fear and joy were associated with temperament. CONCLUSION : The study provides no support for a negative emotionality bias in ASD. Instead, toddlers with ASD display a muted response to threat and an accentuated response to goal blockage, whereas the ability to express positive emotions appears intact. Negative emotionality and social disability dimensions are independent. The study demonstrates the complexity of EE in ASD and motivates investigations into underlying mechanisms as well as its role in shaping complex phenotypes of affected children.

OBJECTIVE : This study examined variability in autism symptom trajectories in toddlers referred for possible autism spectrum disorder (ASD) who had frequent observations from 14 to 36 months of age. METHOD : In total, 912 observations of the Autism Diagnostic Observation Schedule (ADOS) were obtained from 149 children (103 with ASD) followed from 14 to 36 months of age. As a follow-up to a previous analysis of ADOS algorithm scores, a different analytic approach (Proc Traj) was implemented to identify several courses of symptom trajectories using ADOS Calibrated Severity Scores in a larger sample. Proc Traj is a statistical method that clusters individuals into separate groups based on different growth trajectories. Changes in symptom severity based on individual ADOS items also were examined. RESULTS : Trajectory analysis of overall symptom severity identified 4 clusters (non-spectrum approximately 25% ; worsening approximately 27% ; moderately-improving approximately 25% ; severe-persistent approximately 23%). Trajectory clusters varied significantly in the proportions of confirmatory ASD diagnosis, level of baseline and final verbal and nonverbal abilities, and symptom severity. For the moderately-improving group, social communication improved, whereas restricted and repetitive behaviors were stable over time. Language and verbal and nonverbal communication improved for many children, but several social affect and restricted and repetitive behavior symptoms remained stable or worsened. CONCLUSION : Significant variability in symptom trajectories was observed among toddlers referred for possible ASD. Changes in social and restricted and repetitive behavior domain scores did not always co-occur. Similarly, item-level trajectories did not always align with trajectories of overall severity scores. These findings highlight the importance of monitoring individual symptoms within broader symptom domains when conducting repeated assessments for young children with suspected ASD.

OBJECTIVE : The diagnosis of autism spectrum disorder (ASD) has been found to be remarkably stable but few studies have followed children not initially diagnosed with ASD beyond 3 years of age to examine late or delayed diagnoses. The present study used a prospective familial-risk design to identify children who had undergone multiple comprehensive assessments in preschool and were determined to be negative for ASD only to meet criteria for ASD when tested in middle childhood. METHOD : Data were pooled across 3 research teams studying later-born siblings of children with ASD. Fourteen children met inclusion criteria for the late-diagnosed group and were compared with a large sample of high- and low-risk siblings from the same sites who had ASD or typical development (TD) outcomes at 3 years of age. RESULTS : As a group, the late-diagnosed children scored between the TD and ASD groups on most measures administered at 3 years and differed significantly from the ASD group on most measures. However, there was significant heterogeneity among the late-diagnosed cases. Seven showed very little evidence of ASD in preschool, whereas 7 demonstrated subtle, subthreshold symptomatology. CONCLUSION : Some children with ASD might present with a subtle phenotype early in life or show a prolonged time course of symptom development. This emphasizes the need for screening and surveillance schedules that extend past 36 months and continued evaluation of any child who presents with atypical early development and/or high-risk status. The findings also shed light on reasons why the mean age of ASD diagnosis remains older than 4 years.

OBJECTIVE : The serotonin (5-hydroxytryptamine [HT]) system has long been implicated in autism spectrum disorder (ASD). Whole-blood 5-HT level (WB5-HT) is a stable, heritable biomarker that is elevated in more than 25% of children with ASD. Recent findings indicate that the maternal 5-HT system may influence embryonic neurodevelopment, but maternal WB5-HT has not been examined in relation to ASD phenotypes. METHOD : WB5-HT levels were obtained from 181 individuals (3-27 years of age) diagnosed with ASD, 99 of their fathers, and 119 of their mothers. Standardized assessments were used to evaluate cognitive, behavioral, and language phenotypes. RESULTS : Exploratory regression analyses found relationships between maternal WB5-HT and nonverbal IQ (NVIQ), Autism Diagnostic Interview-Revised (ADI-R) Nonverbal Communication Algorithm scores, and overall adaptive function on the Vineland Adaptive Behavior Scales-II. Latent class analysis identified a three-class structure in the assessment data, describing children with low, intermediate, and high severity across measures of behavior, cognition, and adaptive function. Mean maternal WB5-HT differed across classes, with the lowest maternal WB5-HT levels seen in the highest-severity group (Welch F2,46.048 = 17.394, p < .001). Paternal and proband WB5-HT did not differ between classes. CONCLUSION : Maternal WB5-HT is associated with neurodevelopmental outcomes in offspring with ASD. Prospective, longitudinal studies will be needed to better understand the relationship between the function of the maternal serotonin system during pregnancy and brain development. Further studies in animal models may be able to reveal the mechanisms underlying these findings.

In their Translations article in the January issue of the Journal, Turban and van Schalkwyk provide a critical evaluation of the recently published literature on co-occurring gender dysphoria (GD) and autism spectrum disorder (ASD).(1) In addition, they refer to this flux in interest as part of a larger increase in publications on transgender people, which are mostly reviews and do not contain new data. Given the low-grade evidence in this field for most clinical recommendations,(2) good-quality research is of great relevance. We support the debate on the GD-ASD literature and acknowledge that translations of the findings to the lay press such as "Do transgender children just have autism ?" are not helpful. Also, we agree with many of the limitations brought forward by the authors and acknowledge that, at present, sound underlying evidence for a GD-ASD link is lacking. However, we believe that some nuance in argumentation could help forward the debate of this clinically important topic.

Turban and van Schalkwyk assert in their Translations article, "’Gender Dysphoria’ and Autism Spectrum Disorder : Is the Link Real ?" that an over-representation of autism spectrum disorder (ASD) in gender dysphoria is unsupported based on current evidence. Turban and van Schalkwyk discuss 7 of the currently 19 available empirical studies (excluding reviews and case reports) of the over-occurrence of ASD and/or autism traits with gender dysphoria/diversity. They are correct to note that some ASD screeners may lack specificity ; that is, a clinical-range total score could indicate non-ASD-related mental health conditions or other developmental difference. However, they do not account for the 7 available studies which specifically report rates of clinical diagnoses of ASD among unselected gender-diverse samples. We suggest also that many of the studies that assess ASD-symptoms in gender-diverse groups are more convincing than suggested by Turban and van Schalkwyk because they employ measures assessing the multi-dimensionality of ASD symptoms and report significant elevations not only for socially-related symptoms but also for the various components of restricted and repetitive behaviors and interests (RRBI) core to ASD. We come together to write this response as gender clinicians and researchers, autism clinicians and researchers, and key stakeholders, including autistic and autistic transgender self-advocates. We work and live with the co-occurrence of autism and gender diversity on a daily basis, and we are concerned that perpetuating misunderstanding about the co-occurrence places individuals at risk.